Taking on a new process technology, such as an expression system, involves regulatory uncertainty. How will the FDA and other regulatory authorities react to the new technology? Will adopting new technologies cause unacceptable delays in obtaining approvals? Further uncertainty comes from deciding who should do, and pay for, the pioneering regulatory work: the technology developer or licensor, the early product developer, or both?

"If the regulatory submission is for a known process or expression system, the regulatory agencies can review it quickly," says Jim Bingham, PhD, senior director of Development at Amplimmune, Inc. (Rockville, MD). "If it's for a novel technology with no history, such as an untested expression system, it may require a significant evaluation to manage risk and safety. Coming into it, [the regulators'] perception of the innovators can be, 'These guys are cowboys.'"

Indeed, the first companies pioneering adoption of a new manufacturing technology will almost certainly deal with some delays in approvals by the FDA, the EMEA, and others.3 Even if the product produced in a new system may be better (e.g., by having greater consistency, purity, potency, or safety), caution on the part of regulators about new developments is a necessary part of the regulatory system. At the moment, there are insufficient precedents to enable calculation of likely approval delays caused by adopting new manufacturing technologies.

Thus, pioneering the regulatory approval of a biological product manufactured using a novel expression system can be daunting, even for the most experienced regulatory manager.1 Many in the industry feel that the regulatory challenges involved do not warrant the benefits of modifying old manufacturing processes. After all, the standard expression systems, E. coli, Chinese hamster ovary (CHO) cells, and Saccharomyces cerevisiae, which are used for about 90% of currently marketed recombinant protein and monoclonal antibody products, perform adequately. So why change?2

This thinking leads to a logical pack instinct, in which companies wait for a critical mass before adopting new technologies for commercial production. But if no one is willing to take the risk, that critical mass will never be reached. This catch 22 faces those who consider adopting almost any new biopharmaceutical manufacturing technology. As a result of such concerns, many new expression systems now commonly used in research have yet to make it to large-scale manufacture.

IN A MATURING INDUSTRY, INNOVATION IS NOT AN OPTION

Nonetheless, no high-tech industry can afford to ignore new and better technologies, and biotech is no exception. There are hundreds of new and long-ignored expression systems using novel host organisms and technologies in various states of development and industry adoption.1 These platforms can offer many advantages, such as lower costs, higher yields, quicker turnaround or continuous manufacture, increased simplicity of expression and purification, less expensive equipment and infrastructure, and simpler and more rapid scale-up.1

REGULATORY TRAIL BLAZERS

Because of these advantages, a few companies are finding the organizational fortitude to be regulatory trailblazers. For example, the first product manufactured using transgenic animals, recombinant human antithrombin (Atryn, from GTC Biotherapeutics) received FDA approval in early 2009; and a recombinant human papillomavirus (HPV) vaccine expressed in insect cells using baculovirus vectors (Cervarix, from GlaxoSmithKline), is pending at the FDA and already approved in the European Union. Many other recombinant proteins using novel expression systems are in development, mostly at early stages. This includes products being developed by expression systems' developers and their partners who intend to prove commercial feasibility of their technologies through actual product manufacture.

In addition, many contract manufacturing organizations (CMOs) are starting to adopt and offer new expression technologies, at least in early-stage R&D. This will likely expand as products progress in development pipelines and their manufacture is further scaled-up.

IMPACT OF BIOSIMILARS

Many of the products expected to enter the market using new expression systems are biosimilars and follow-on proteins. Biosimilar developers are motivated by manufacturing costs, so they may be a little more willing to adopt state-of-the-art technologies, which often make production cheaper and faster. In addition, new expression technologies may make it possible to produce drugs that are of higher quality than the innovator products. Many of these biosimilars companies want to be able to claim that their products are not just cheaper, but also better—more consistent, purer, more potent—than their reference products.